13 results on '"Herrero Del Valle, Alba"'
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2. Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling
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van der Stel, Anne-Xander, Gordon, Emily R., Sengupta, Arnab, Martínez, Allyson K., Klepacki, Dorota, Perry, Thomas N., Herrero del Valle, Alba, Vázquez-Laslop, Nora, Sachs, Matthew S., Cruz-Vera, Luis R., and Innis, C. Axel
- Published
- 2021
- Full Text
- View/download PDF
3. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
- Author
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Yu, Qin, Herrero del Valle, Alba, Singh, Rahul, and Modis, Yorgo
- Published
- 2021
- Full Text
- View/download PDF
4. Ornithine capture by a translating ribosome controls bacterial polyamine synthesis
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Herrero del Valle, Alba, Seip, Britta, Cervera-Marzal, Iñaki, Sacheau, Guénaël, Seefeldt, A. Carolin, and Innis, C. Axel
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- 2020
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5. Contrasting functions of ATP hydrolysis by MDA5 and LGP2 in viral RNA sensing
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Singh, Rahul, primary, Wu, Yuan, additional, Herrero del Valle, Alba, additional, Leigh, Kendra E, additional, Cheng, Mark T. K., additional, Ferguson, Brian J, additional, and Modis, Yorgo, additional
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- 2023
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6. Détection de métabolites par des peptides d'arrêt ribosomaux
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Herrero del valle, Alba, Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux, and Axel Innis
- Subjects
Détection des métabolites ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Arrest peptide ,Antibiotique ,Antibiotic ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Ribosome ,Metabolite sensing ,Cryo-EM ,Peptide d'arrêt - Abstract
Bacteria need to rapidly adapt to the changing environment by adjusting their gene expression patterns and enzymatic activities. In most cases, the variations in their habitat involve small molecules that bacteria are able to sense and respond to. The ribosome, the machinery of the cell that catalyzes peptide bond formation, is able to detect metabolites or antibiotics to regulate gene expression via nascent-chain mediated translational arrest. In this mechanism, the peptide that is being translated (arrest peptide) stalls the ribosome by interacting with the walls of the ribosomal tunnel, the cavity through which it reaches the cytoplasm. The arrest may depend solely on the sequence of the peptide or need a small molecule to be triggered. Ribosomal stalling in turn, controls the expression of a gene that is located downstream on the same mRNA. Despite previous biochemical and structural studies, the exact mechanism of sensing of small metabolites by the nascent chain is still unknown. My PhD work focused on: (1) understanding how small molecules are sensed by ribosomal arrest peptides, and (2) a special case of ligand-dependent translational arrest: drug sensing by short arrest peptides.To address the first issue, I studied biochemically and structurally a novel L-ornithine sensing arrest peptide (SpeFL) encoded upstream the speF operon in Escherichia coli. The cryo-EM structure that I solved revealed how a small molecule is sensed by a ribosome nascent chain complex in a highly specific manner. Besides, I showed that the mechanism of induction of the downstream gene speF involves ribosomal arrest at speFL preventing premature Rho-dependent transcriptional termination.On the second part of my thesis, I focused on how a ribosome-targeting antibiotic, erythromycin, is sensed by a short arrest peptide. Erythromycin is able to block translation in a sequence dependent manner, with the (+)X(+) motif being the main stalling motif. Previously published biochemical data suggest that steric and static hindrance caused by the first positively charged amino acid prevents the addition of the second one arresting the ribosome. I solved the cryo-EM structure of a ribosome arrested by an MKFR peptide in the presence of erythromycin that shows otherwise and opens up further investigation on the matter.; Les bactéries doivent s'adapter rapidement aux modifications de leur environnement en ajustant leur modèle d'expression génétique et leurs activités enzymatiques. Dans la plupart des cas, les variations de leur habitat impliquent de petites molécules que les bactéries peuvent détecter et auxquelles elles peuvent réagir. Le ribosome, la machinerie de la cellule qui catalyse la formation de la liaison peptidique, est capable de détecter les métabolites ou les antibiotiques afin de réguler l'expression des gènes, où le peptide naissant au sein du ribosome est capable d’induire l’arrêt de la traduction. Dans ce mécanisme, le peptide en cours de traduction (peptide d'arrêt) bloque le ribosome en interagissant avec les parois du tunnel ribosomal correspondant à la cavité par laquelle le peptide atteint le cytoplasme. L'arrêt peut dépendre uniquement de la séquence du peptide ou bien nécessiter la liaison d’une petite molécule. L’arrêt du ribosome en cours de traduction contrôle à son tour l'expression sur le même ARNm d'un gène situé en aval. Malgré plusieurs études biochimiques et structurales antérieures, le mécanisme exact de détection de ces petits métabolites par le peptide d’arrêt est encore inconnu. Mon travail de doctorat a porté sur : (1) comprendre comment de petites molécules sont détectées par les peptides d'arrêt ribosomaux, et (2) un cas particulier d'arrêt de la traduction dépendant du ligand : la détection des antibiotiques par des peptides d'arrêt courts.Pour répondre au premier problème, j'ai étudié biochimiquement et structurellement un nouveau peptide d'arrêt (appelé SpeFL) qui détecte l’ornithine (un petit métabolite) et qui est codé en amont de l'opéron speF chez Escherichia coli. La structure cryo-EM que j'ai résolue a révélé comment l’ornithine est détectée de manière très spécifique par un complexe ribosomal en cours de traduction. De plus, j'ai montré que le mécanisme d'induction du gène en aval speF implique un arrêt du ribosome au niveau de speFL empêchant ainsi une terminaison prématurée de la transcription Rho-dépendante.Dans la deuxième partie de ma thèse, je me suis concentrée sur la façon dont un antibiotique ciblant les ribosomes, l'érythromycine, est détecté par un peptide d'arrêt court. L'érythromycine est capable de bloquer la traduction de manière séquence-dépendante, où le motif (+)X(+) est le motif principal de blocage. Des données biochimiques publiées antérieurement suggèrent que l'encombrement stérique et électrostatique causé par le premier acide aminé chargé positivement (+) empêche l'addition du second, arrêtant ainsi le ribosome en cours de traduction. La résolution de la structure cryo-EM d'un ribosome arrêté par un peptide MKFR en présence d'érythromycine suggère le contraire, ce qui ouvre la voie à d'autres recherches sur le sujet.
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- 2019
7. Prospects for antimicrobial development in the cryo-EM era – a focus on the ribosome
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Herrero del Valle, Alba, primary and Innis, C Axel, additional
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- 2020
- Full Text
- View/download PDF
8. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
- Author
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Yu, Qin, Herrero del Valle, Alba, Singh, Rahul, and Modis, Yorgo
- Subjects
3. Good health - Abstract
Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease., Nature Communications, 12 (1), ISSN:2041-1723
9. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
- Author
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Yu, Qin, Herrero Del Valle, Alba, Singh, Rahul, and Modis, Yorgo
- Subjects
3. Good health - Abstract
Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease., Human Frontier Science Program
10. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
- Author
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Yu, Qin, Herrero Del Valle, Alba, Singh, Rahul, and Modis, Yorgo
- Subjects
82/29 ,631/250/262/2106/2518 ,631/250/256/2515 ,631/45/500 ,101/28 ,article ,82/83 ,631/45/173 ,631/45/535/1258/1259 ,3. Good health ,96/95 - Abstract
Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease.
11. Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling
- Author
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van der Stel, Anne-Xander, Gordon, Emily R., Sengupta, Arnab, Martínez, Allyson K., Klepacki, Dorota, Perry, Thomas N., Herrero del Valle, Alba, Vázquez-Laslop, Nora, Sachs, Matthew S., Cruz-Vera, Luis R., and Innis, C. Axel
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Models, Molecular ,Protein Conformation, alpha-Helical ,Binding Sites ,Escherichia coli Proteins ,Science ,Cryoelectron Microscopy ,Tryptophan ,Gene Expression Regulation, Bacterial ,Peptide Chain Termination, Translational ,RNA, Transfer, Amino Acyl ,Ribosome ,Article ,Amino Acid Substitution ,Mutation ,Operon ,Escherichia coli ,Protein Conformation, beta-Strand ,Protein Interaction Domains and Motifs ,Peptide Chain Initiation, Translational ,Ribosomes ,Peptide Termination Factors ,Protein Binding - Abstract
Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp. We show that the TnaC–ribosome complex captures a single L-Trp molecule to undergo termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. Importantly, the L-Trp binding site is not altered by the R23F mutation, suggesting that the relative rates of L-Trp binding and peptidyl-tRNA cleavage determine the tryptophan sensitivity of each variant. Thus, our study reveals a strategy whereby a nascent peptide assists the ribosome in detecting a small metabolite., Bacteria adjust the expression of some of their metabolic enzymes through metabolite-sensing ribosome nascent chain complexes. Here the authors present a cryo-EM structure of an E. coli ribosome stalled during translation of the TnaC leader peptide and propose a model for L-Trp dependent ribosome stalling where L-Trp competes with release factor 2 for binding to the TnaC-ribosome complex.
- Full Text
- View/download PDF
12. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
- Author
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Yu, Qin, Herrero Del Valle, Alba, Singh, Rahul, and Modis, Yorgo
- Subjects
Adenosine Triphosphatases ,Inflammation ,Models, Molecular ,Interferon-Induced Helicase, IFIH1 ,Protein Conformation ,Cryoelectron Microscopy ,Mutation, Missense ,Immunity, Innate ,3. Good health ,Adenosine Triphosphate ,HEK293 Cells ,Humans ,Nucleic Acid Conformation ,RNA, Viral ,Protein Binding ,RNA, Double-Stranded - Abstract
Funder: National Institute for Health Research (NIHR), Funder: Medical Research Council, Funder: Biotechnology and Biological Sciences Research Council, Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease.
13. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
- Author
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Qin Yu, Yorgo Modis, Alba Herrero del Valle, Rahul Singh, Yu, Qin [0000-0001-9265-632X], Herrero Del Valle, Alba [0000-0001-8153-6146], Singh, Rahul [0000-0001-8397-0202], Modis, Yorgo [0000-0002-6084-0429], Apollo - University of Cambridge Repository, and Herrero del Valle, Alba [0000-0001-8153-6146]
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Models, Molecular ,82/29 ,Interferon-Induced Helicase, IFIH1 ,Protein Conformation ,ATPase ,viruses ,General Physics and Astronomy ,medicine.disease_cause ,631/45/173 ,631/45/535/1258/1259 ,Adenosine Triphosphate ,0302 clinical medicine ,ATP hydrolysis ,Interferon ,Adenosine Triphosphatases ,0303 health sciences ,Mutation ,Multidisciplinary ,biology ,Chemistry ,631/45/500 ,article ,food and beverages ,MDA5 ,Chronic inflammation ,3. Good health ,Cell biology ,RNA silencing ,Enzyme mechanisms ,RNA, Viral ,Protein Binding ,medicine.drug ,Science ,Allosteric regulation ,Mutation, Missense ,General Biochemistry, Genetics and Molecular Biology ,96/95 ,03 medical and health sciences ,medicine ,Humans ,82/83 ,RNA, Double-Stranded ,030304 developmental biology ,Inflammation ,631/250/262/2106/2518 ,Cryoelectron Microscopy ,101/28 ,fungi ,RNA ,General Chemistry ,Immunity, Innate ,HEK293 Cells ,631/250/256/2515 ,RIG-I-like receptors ,biology.protein ,Nucleic Acid Conformation ,030217 neurology & neurosurgery - Abstract
Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease., MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA.
- Published
- 2021
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